The EM core of this Program Project has two related purposes - to support instrumentation essential for the research proposed in the four projects of this grant and to facilitate application of the methods being developed in these projects to collaborative and independent efforts. The principal components of the core are the electron microscopy facilities at Harvard Medical School (HMS) and at Brandeis University. The HMS facility will house four FBI microscopes: a Tecnai F20, a Tecnai T12, a CM10, and a Polara F30. The F30, the F20, and the T12 microscopes are equipped with cryo-stages; the F30 and the F20 have field-emission guns. The Brandeis facility also houses four FBI instruments: a Morgagni M268, and EM20, a CM12, and a Tecnai F30. The last three have cryo-stages; the F30 has a field-emission gun and an energy filter. The core supports the operation of these microscopes and the salary of a facilities manager at each location, as well as necessary ancillary equipment. The core also has a computational component. It maintainsand upgrades all standard EM software, including program suites such as FREALIGN, IMAGIC, and SPIDER, through a structural biology computational grid (SBGrid) established by the Center for Molecular and Cellular Dynamics at HMS. Finally, by providing EM and computational facilities, the core allows the P.I.'s of these projects to collaborate with other groups at various institutionsand to train postdoctoral fellows and students in the relevant methods. Relevance: Electron microscopy is the key experimental tool that bridges between low- and high-resolution structural methods. Large assemblies will be targets of future interventions in human disease, and electron microscopy will be central for relating structure and function of these complexes